Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with aging. Insight into the molecular basis of AD progression has been facilitated by the study of rare familial mutations which result in altered proteolytic processing of amyloid precursor protein (APP). One of the proteolytic products of APP, A2 peptide, is prone to aggregation and likely contributes to neuronal loss and cognitive dysfunction in AD. Unlike familial cases of AD, the underlying causes of late-onset AD are poorly understood. Genetic studies indicate that the UBQLN1 gene may be linked to late-onset AD. The protein product of the UBQLN1 gene, ubiquilin-1, is a modular protein which contains ubiquitin-like and ubiquitin-associated domains. Ubiquilin-1 also contains Sti1 domains implicated in protein-protein interactions and co-chaperone activity. These domains are present in several co-chaperone proteins, some of which have intrinsic molecular chaperone activity. A chaperone function for ubiquilin has not been demonstrated. We have found that ubiquilin has intrinsic molecular chaperone activity and binds to the cytosolic domain of APP. This binding directly modulates both the maturation and degradation of APP. The central hypothesis of this proposal is that ubiquilin is a key quality control molecule for APP folding and maturation: ubiquilin binds to and exerts chaperone activity on folding-competent APP species along the secretory pathway, whereas it targets misfolded APP to the proteasome system for degradation. This hypothesis will be addressed in three Specific Aims. In the first Aim, we will determine whether ubiquilin functions as a molecular chaperone for APP or APP fragments. In the second Aim, we will determine whether ubiquilin targets APP and/or APP proteolytic fragments for proteasomal degradation. Finally, in the third Aim we will determine whether ubiquilin modulates APP maturation and subsequent toxicity. Biochemical assays and live cell imaging will be used to determine how ubiquilin modulates APP maturation and degradation in cell lines and primary cortical neurons. We propose a novel function for ubiquilin as a molecular chaperone and hypothesize this function is critical for regulating the maturation, degradation and toxicity of APP. These studies may provide fundamental insights into the mechanistic basis of ubiquilin function in late-onset Alzheimer's disease. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most prevalent cause of dementia associated with aging. The molecular basis of AD progression in the aging population is poorly understood. This proposal will address the physiologic mechanisms by which the UBQLN1 gene product modulates amyloid precursor protein aggregation and toxicity, thus potentially revealing new therapeutic targets for this common disease. [unreadable] [unreadable]